Background <p>Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by disruption of the alveolar-capillary barrier, non-cardiogenic pulmonary edema, and severe hypoxemia. Its core pathophysiology involves uncontrolled systemic inflammation and oxidative stress injury. Mechanical ventilation remains the primary respiratory support strategy for ARDS, but may aggravate lung injury and trigger stress responses. Therefore, developing individualized sedation strategies to regulate stress and inflammatory responses is critical to improving patient outcomes. This study aimed to compare the sedative effects of remimazolam besylate and dexmedetomidine in mechanically ventilated ARDS patients, and to evaluate their dynamic impact on stress markers and inflammatory cytokines, in order to explore their differences in immunomodulation.</p> Methods <p>This single-center, prospective, randomized controlled trial enrolled ICU patients who met the diagnostic criteria for ARDS and required mechanical ventilation for ≥ 72 h. A total of 60 patients were randomly assigned to receive either dexmedetomidine or remimazolam besylate, with both groups receiving standard analgesia and continuous infusion of the assigned sedative. Sedation depth was assessed using the Richmond Agitation-Sedation Scale (RASS), and stress markers and inflammatory cytokines were measured for comparative analysis.</p> Results <p>Baseline characteristics were comparable between the two groups. At 48 h post-administration, the cortisol level in the remimazolam group was significantly lower than in the dexmedetomidine group (<i>P</i> = 0.013). Regarding inflammatory cytokines, IL-4 and IL-10 levels were lower in the remimazolam group, while IL-6 was lower in the dexmedetomidine group. Additionally, IL-4 and IL-17 levels significantly increased in the dexmedetomidine group after 48 h (<i>P</i> &lt; 0.05), suggesting its potential role in promoting Th2 immune responses and anti-inflammatory pathways. There was no significant difference in sedation depth between the two groups, and no serious adverse events were reported.</p> Conclusion <p>Both remimazolam besylate and dexmedetomidine provide effective sedation in patients with ARDS; however, they differ significantly in their effects on stress modulation and inflammatory regulation. Remimazolam besylate may reduce stress responses primarily by suppressing activation of the hypothalamic–pituitary–adrenal (HPA) axis, while dexmedetomidine may exert its effects through modulation of Th2 immune responses and inflammatory cytokine release. These findings offer new evidence to support individualized sedation strategies in the management of ARDS.</p>